Intensive Weekly Chemotherapy for Advanced Gastric Cancer Using Fluorouracil, Cisplatin, Epi-Doxorubicin, 6S-Leucovorin, Glutathione, and Filgrastim: A Report From the Italian Group for the Study of Digestive Tract Cancer

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Background

Gastric cancer is the second most common cause of cancer death in the world. Only 10% are limited to the stomach at the time of diagnosis. Eighty percent of these patients have positive lymph nodes, 40% have peritoneal spread and 33% liver metastases at the time of diagnosis. Five-year survival data is abysmal at 5 - 15%. Therefore, due to the high incidence of metastases at diagnosis, much effort has been placed into optimizing systemic therapy.

Kelsen et al from Memorial Sloan Kettering Cancer Center reviewed the literature for the regimens that have been used for gastric cancer. Single agents utilized have been 5-FU, Mitomycin C, Adriamycin, and Cisplatin with response rates of 17 - 30%. Combination regimens include 5-FU/Adriamycin/Cisplatin (FAP), 5-FU/Adriamycin/Mitomycin C (FAM), etc. These treatments have a response rates of 30 - 36%. There is some excitement about Etoposide/Adriamycin/Cisplatin (EAP) with response rates of 64 - 70%, but median survivals are still only 9 - 18 months which are very similar to previous data with other regimens.

The Italian Group for the Study of Digestive Tract Cancer has now published their results of the pilot prospective study of intensive weekly Cisplatin, 5-FU, Leucovorin, epi-Doxirubicin, Glutathione and GCSF on 105 patients with unresectable locally advanced or metastatic disease with or without local resection of gastric primary lesion.

Materials and Methods

The selection of the chemotherapy was based on a number of factors. The combination of Cisplatin, 5-FU and epi-Doxirubicin (Adriamycin) had been shown to be an effective regimen in England, thus it was utilized here. Epi-Doxirubicin instead of Doxirubicin was because of a reported decreased incidence of mucositis. Leucovorin was used to enhance 5-FU's effect. Glutathione has been shown to reduce risk of Cisplatin induced neurotoxicity. Filgrastim was used to increase WBC and avoid neutropenia. The chemotherapy was given on the first day of each week. Initially, patients who responded or had stable disease after 8 weeks of treatment, would receive an additional 6 weeks. The Cisplatin was 40 mg/m2, 5-FU of 500 mg/m2 and epi-Doxirubicin of 35 mg/m2. Glutathione (1.5 mg/m2) was given on that day along with leucovorin (250 mg/m2). Filgrastim (GCSF) was given on the days when no chemotherapy was given.

Results

From June of 1993 to September 1995, 10 institutions treated 105 enrolled patients with this regimen. Median follow up was 26 months. Objective tumor response was seen in 62% (65 of 105) with 17% (18 patients) achieving a clinical complete response. There were partial or complete responses (50% or more regression) in the metastatic lesions at various sites: 58% of 38 patients with liver metastases, 77% of 31 patients with positive lymph nodes, 55% of 38 patients with peritoneal metastases and 66% of 6 patients with lung metastases. Eighty-five patients had either stable disease or a clinical response. Twenty patients had only the initial eight weeks of treatment. Overall survival was poor, as to be expected from this population. Median survival was 11 months with one year rate of 42%, but a two year rate of 5%. Only 5% grade 4 leukopenia was seen and no grade 5 or fatal toxicities were seen.

Discussion

The regimen proposed and studied by the Italian group has shown some promise, but survival continues to be abysmal despite a relatively high response rate. Such is the nature of this disease. It appears to have a good tolerance profile, though. In reference to the epi-Doxirubicin, there were only 3 grade mucositis events. The amount of neurotoxicity from Cisplatin seemed to be well controlled (only 3 grade 1-2 neuropathies), perhaps due to the utilization of Glutathione. The Italian group is proposing to begin randomized trials to look at the possibility of utilizing this as adjuvant or neo-adjuvant treatment in addition to surgery and/or radiation.